Faecal Microbiota Transplantation for Insomnia Disorder: a Randomized, Double-blind, Placebo-controlled Trial

Insomnia disorder is characterized by difficulty initiating or maintaining sleep, or early morning awakening accompanied by daytime symptoms such as irritability or fatigue. It is one of the most prevalent health problems in the population and in clinical practice, with more than one-third of adults experience transient insomnia at some point in their lives. In about 40% of cases, insomnia can develop into a more chronic condition. The COVID-19 pandemic has further aggravated sleep problems, with a reported global prevalence of sleep disturbances reaching 40-49%. The social, economic, psychological and physical implications of insomnia disorder are substantial, with evidence linking the condition to an increased risk of hypertension, cardiovascular disease, anxiety, and depression, as well as impaired quality of life, work absenteeism, work-related accidents, poor work efficiency, and family dysfunction.

Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. Pharmacological treatment is common in practice and widely used for the management of insomnia. A recent meta-analysis suggested that Eszopiclone and Lemborexant had the best profile in terms of efficacy, acceptability, and tolerability. However, Eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Many licensed drugs (including benzodiazepines, Z-hypnotics and dual orexin receptor antagonist, DORA) are prescribed as effective short-term treatment of insomnia but some are associated with poor tolerability, or the information about long-term safety effects is not available. Alternatively, cognitive behavioral therapy for insomnia (CBT-I), has been recommended as the first-line treatment for chronic insomnia in adults of any age according to the American and European guidelines. But issues of accessibility, compliance/adherence, and moderate response also pose limit the practicality and applicability of CBT-I.

Growing evidence indicates that the microbiota-gut-brain axis contributes to the regulation of sleep behavior both directly and indirectly and may play a critical role in the etiology and pathogenesis of sleep disorders. Sleep loss is capable of altering the gut microbiota composition through increased hunger and decreased physical activity, immunomodulation, or hypothalamus-pituitary-adrenal (HPA) axis activation and subsequent intestinal barrier disruption. Conversely, the gut microbiome is capable of altering sleep through somnogenic lipopolysaccharide (LPS) and Muramyl peptides translocation, vagal afferent excitation in response to enteric LPS, regulation of enterochromaffin cell serotonin production, and inflammatory cytokine regulation. Consequently, gut microbiota modulation is a potential therapy for insomnia.

According to a preclinical study, transplantation of the gut microbiota from mice with sleep disorder into normal mice induced microglia overactivation and neuronal apoptosis in the hippocampus, cognitive decline, and colonic microbiota disorder. Moreover, a human study found that fecal microbiota transplantation (FMT) from healthy donors improved sleep and also ameliorated depression and anxiety in patients with irritable bowel syndrome (IBS). Another study demonstrated that FMT led to a decrease in the scores of the five components of Pittsburgh Sleep Quality Index (PSQI) in 52 IBS patients with poor sleep quality, including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, and sleep disturbances. A clinical study showed significantly lower Sleep Disturbance Scale for Children (SDSC) scores in children with autism after FMT, whilst a retrospective study also indicated that FMT could significantly improve the sleep disorder scores in the autistic children with constipation. According to a real world study, FMT significantly ameliorated the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), and quality of life in patients with chronic insomnia. The results from one previous study also demonstrated that FMT could alleviate post-COVID insomnia.

In this randomised, double-blind, placebo-controlled trial, the investigators aim to assess the efficacy of FMT in improving insomnia disorder. The investigators hypothesize that FMT is a safe and effective treatment for insomnia disorder.